The present invention relates to a process for preparing 3-cyano-2,4-dihalogeno-5-fluoro-benzoic acids, to intermediates for carrying out the process and to processes for preparing these intermediates.
3-Cyano-2,4-dichloro-5-fluoro-benzoic acid is known from DE-A-3 702 393. It is prepared from 3-amino-2,4-dichloro-5-fluoro-benzoic acid by diazotization and reaction of the diazonium salt with cyanide salts. This process is unfavourable, in particular when it is carried out on a relatively large scale.
The present invention provides
1. Process for preparing 3-cyano-2,4-dihalogeno-5-fluorobenzoic acids of the formula (I) 
in which
X and Y independently of one another each represent halogen by hydrolytic cleavage of
a) 3-cyano-2,4-dihalogeno-5-fluorobenzamides of the formula (II) 
xe2x80x83in which
X and Y independently of one another each represent halogen, or
b) 1,3-dicyano-2,4-dihalogeno-5-fluorobenzenes of the formula (III) 
xe2x80x83in which
X and Y independently of one another each represent halogen, or
c) 3-cyano-2,4-dihalogeno-5-fluorobenzoic esters of the formula (IV) 
xe2x80x83in which
X and Y independently of one another each represent halogen and
R represents C1-4-alkyl which may optionally be substituted.
2. The novel compounds of the formulae (II) 
and (IV) 
in which
X and Y independently of one another each represent halogen and
R represents C1-4-alkyl which may optionally be substituted,
except for methyl3-cyano-2,4,5-trifluorobenzoate.
3. Process for preparing 3-cyano-2,4-dihalogeno-5-fluoro-benzamides of the formula (II) 
or esters of the formula (IV) 
characterized in that 1,3-dicyano-2,4-dihalogeno-5-fluorobenzenes of the formula (III) 
xe2x80x83in which
X and Y are each as defined above,
are hydrolyzed in the presence of water or in the presence of alcohols.
4. The novel compounds of the formula (III) 
in which
X and Y represent different radicals from the group consisting of fluorine and chlorine, or both radicals represent chlorine.
5. Process for preparing the compounds of the formula (III) 
in which
X and Y represent different radicals from the group consisting of fluorine and chlorine,
characterized in that 1,2,4-trifluoro-3,5-dicyanobenzene(2,4,5-trifluoro-isophthalonitrile) is reacted with a metal halide.
1,2,4-Trifluoro-3,5-dicyanobenzene and its preparation are known from EP-A-307 897.
In the above formulae, X and Y each preferably represent fluorine or chlorine. In the compounds of the formulae (II) and (IV), they particularly preferably represent identical radicals fluorine or chlorine.
Among the compounds of the formula (III), particular preference is given to 2,4-dichloro-5-fluoroisophthalonitrile.
R preferably represents methyl, ethyl, propyl or benzyl.
If 3-cyano-2,4,5-trifluorobenzamide is used as starting material in the process a) for preparing 3-cyano-2,4,5-trifluorobenzoic acid, the reaction can be illustrated by the following formula scheme: 
The amides of the formula (II) used as starting materials are novel. Their preparation is described further below.
The hydrolysis is carried out in the presence of acids and water. Suitable for use as acids are organic and inorganic strong acids. Examples which may be mentioned are HCl, HBr, sulphuric acid, methanesulphonic acid, trifluoromethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid and strongly acidic ion exchangers in the presence of water.
The solvent used can be an excess of the acid used as reagent, or an organic solvent. Suitable organic solvents are acids, such as formic acid, acetic acid, propionic acid, ethers, such as dimethoxyethane, dioxane, ketones, such as acetone, butanone.
The reaction components may be added in any order. The mixture is subsequently heated to the required temperature.
The reaction temperature is in the range from 0 to 200xc2x0 C., preferably from 20 to 150xc2x0 C.
The reaction can be carried out under atmospheric pressure or under a pressure of from 0 to 50 bar, preferably from 0 to 6 bar.
The products are filtered off from the reaction mixture, if appropriate after dilution with water. If a large excess of acid or a solvent is used, it may be advantageous to carry out a distillation and to isolate the product by extraction.
If 4-chloro-2,5-difluoro-isophthalonitrile is used as starting material for preparing 4-chloro-2,5-difluoro-3-cyanobenzoic acid according to process 1b), the reaction can be illustrated by the reaction scheme below: 
2,4,5-Trifluoro-isophthalonitrile is known from the literature (EP-A-307 897). 2,4-Dichloro-5-fluoro-isophthalonitrile is novel. Its preparation is described further below.
The hydrolysis with acids is carried out in the presence of water. Suitable for use as acids are organic and inorganic strong acids. Examples which may be mentioned are HCl, HBr, sulphuric acid, methanesulphonic acid, trifluoromethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid and strongly acidic ion exchangers in the presence of water.
The solvent used can be an excess of the acid used as reagent, or an organic solvent. Suitable organic solvents are acids, such as formic acid, acetic acid, propionic acid, ethers, such as dimethoxyethane, dioxane, ketones, such as acetone, butanone.
The reaction components may be added in any order. The mixture is subsequently heated to the required temperature.
The reaction temperature is in the range from 0 to 200xc2x0 C., preferably from 20 to 150xc2x0 C.
The reaction can be carried out under atmospheric pressure or under a pressure of from 0 to 50 bar, preferably from 0 to 6 bar.
The products are filtered off from the reaction mixture, if appropriate after dilution with water. If a large excess of acid or a solvent is used, it may be advantageous to carry out a distillation and to isolate the product by extraction.
If methyl 3-cyano-2,4,5-trifluoro-benzoate is used as starting material in the process 1c) for preparing 3-cyano-2,4,5-trifluorobenzoic acid, the reaction can be illustrated by the formula scheme below: 
The esters of the formula (IV) used as starting materials are novel. Their preparation is described further below.
The hydrolysis is carried out in the presence of acids and water. Suitable for use as acids are organic and inorganic strong acids. Examples which may be mentioned are HCl, HBr, sulphuric acid, methanesulphonic acid, trifluoromethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid and strongly acidic ion exchangers in the presence of water.
The solvent used can be an excess of the acid used as reagent, or an organic solvent. Suitable organic solvents are acids, such as formic acid, acetic acid, propionic acid, ethers, such as dimethoxyethane, dioxane, ketones, such as acetone, butanone.
The reaction components may be added in any order. The mixture is subsequently heated to the required temperature.
The reaction temperature is in the range from 0 to 200xc2x0 C., preferably from 20 to 150xc2x0 C.
The reaction can be carried out under atmospheric pressure or under a pressure of from 0 to 50 bar, preferably from 0 to 6 bar.
The products are extracted from the reaction mixture, if appropriate after dilution with water. If a large excess of acid or a solvent is used, it may be advantageous to carry out a distillation.
As already mentioned, the compounds of the formula (IV) are novel.
If 2,4-dichloro-5-fluoro-isophthalonitrile is used as starting material for their preparation according to process 3), the reaction can be represented by the formula scheme below: 
The reaction proceeds via the iminoester intermediate and its hydrolysis with water. The formation of the corresponding amide is observed as a side reaction. If no water is added, the amide formation becomes the predominant reaction (see below).
2,4,5-Trifluoro-isophthalonitrile is known from the literature (EP-A-307 897). 2,4-Dichloro-5-fluoro-isophthalonitrile is novel, its preparation is described further below.
The compound of the formula (II) is prepared by hydrolysis of the corresponding dinitriles with acids in the presence of water and alcohols.
The reaction is carried out in the presence of from 1 to 10 equivalents of water and primary and secondary aliphatic alcohols. Preference is given to methanol, ethanol, propanol and butanol. Acids used can be organic and inorganic strong acids, such as HCl, HBr, sulphuric acid, methanesulphonic acid, trifluoromethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid and strongly acidic ion exchangers.
In addition to from I to 10 mol of alcohol, it is also possible to employ from 1 to 10 mol of water per mole of dinitrile.
The reaction can be carried out in the presence or absence of solvent. The solvent used can be an excess of the alcohol used as reagent, or an inert organic solvent. Suitable inert solvents are: all inert organic solvents, such as hydrocarbons, for example pentane, hexane, heptane, petroleum ether, benzine, ligroine, benzene, toluene; halogenated hydrocarbons, for example dichloromethane, chloroform, chlorobenzene, dichlorobenzene, trichloroethane; ethers, for example diethyl ether, dipropyl ether, dibutyl ether, ethylene glycol dimethyl ether, diethylene glycol diethyl ether.
Dintrile and alcohol are initially charged and acid is added, and the water is then added. However, it is also possible to initially charge the water required for the reaction directly.
The reaction temperature is in the range from xe2x88x9220 to 150xc2x0 C. Preference is given to temperatures from 10 to 100xc2x0 C.
The reaction can be carried out at atmospheric pressure or elevated pressure of from 0 to 50 bar. Preference is given to a pressure from 0 to 6 bar.
The reaction mixture is diluted with water and extracted. If a large excess of alcohol or an inert solvent were used, the solvent can be distilled off first. Any amide formed as reaction by-product can be separated off.
As already mentioned, the compounds of the formula (II) are novel.
If 2,4,5-trifluoro-isophthalonitrile is used as starting material for their preparation according to process 3), the reaction can be represented by the formula scheme below: 
The reaction proceeds via the intermediate imino esters, from which the amides are formed by elimination of the alkyl radical.
2,4,5-Trifluoro-isophthalonitrile is known from the literature (EP-A-307 897). 2,4-Dichloro-5-fluoro-isophthalonitrile is novel, the preparation is described further below.
The reaction is carried out with primary or secondary aliphatic alcohols in the presence of acids. Preference is given to methanol, ethanol, propanol and butanol. Particular preference is given to methanol. Suitable for use as acids are organic and inorganic strong acids, such as HCl, HBr.
From 1 to 10 mol of alcohol can be used per mole of dinitrile.
The reaction can be carried out in the presence or absence of solvent. The solvent used can be an excess of the alcohol used as reagent, or an inert organic solvent. Suitable inert solvents are: all inert organic solvents, such as hydrocarbons, for example pentane, hexane, heptane, petroleum ether, benzine, ligroine, benzene, toluene; halogenated hydrocarbons, for example dichloromethane, chloroform, chlorobenzene, dichlorobenzene, trichloroethane; ethers, for example diethyl ether, dipropyl ether, dibutyl ether, ethylene glycol dimethyl ether, diethylene glycol diethyl ether.
Dinitrile and alcohol are initially charged, and acid is added.
The reaction temperature is in the range from xe2x88x9220 to 150xc2x0 C. Preference is given to temperatures from xe2x88x920xc2x0 to 100xc2x0 C.
The reaction can be carried out at atmospheric pressure or an elevated pressure of from 0 to 50 bar. Preference is given to a pressure from 0 to 6 bar.
The products are filtered off from the reaction mixture, if appropriate after dilution with water. If a large excess of alcohol or an inert solvent was used, this can be preceded by distillation.
Compounds of the formula (III) in which X and Y do not simultaneously represent F are novel. Starting from 2,4,5-trifluoro-isophthalonitrile, their preparation according to process 5) can be represented by the formula scheme below: 
2,4,5-Trifluoro-isophthalonitrile is known from the literature (EP-A-307 897).
The halogen exchange is carried out by reaction with inorganic chloride salts.
Suitable for use as inorganic chloride salts are MgCl2 and CaCl2. It is also possible to catalyse the reaction, for example using tetraalkylammonium salts, crown ethers, etc.
From 0.5 to 10 mol of inorganic salt are employed per fluorine to be exchanged. Preference is given to from 0.5 to 2 mol.
The reaction can be carried out in the presence or absence of solvent. Suitable solvents are all inert organic solvents, for example pentane, hexane, heptane, petroleum ether, benzine, ligroine, benzene, toluene, dichloromethane, chloroform, chlorobenzene, dichlorobenzene, trichloroethane, ethers, such as dibutyl ether, ethylene glycol dimethyl ether, diethylene glycol diethyl ether, ketones, such as acetone, methyl ethyl ketone, cyclohexanone, and also N-methylpyrrolidinone, dimethyl sulphone, sulpholane.
The substances are mixed and heated to the required temperature. The order of addition is immaterial. Depending on how the reaction is carried out, it is possible to exchange one or two fluorine atoms for chlorine.
The reaction temperature is in the range from 50 to 350xc2x0 C. Preference is given to temperatures from 90 to 250xc2x0 C.
The reaction can be carried out under atmospheric or elevated pressure. If low-boiling solvents are used, it may be favourable to carry out the reaction under elevated pressure. Pressure range: a superatmospheric pressure of from 0 to 100 bar. Preferably: from 0 to 50 bar.
The products are isolated by filtering off the inorganic salts and subjecting the filtrate to fractional distillation. If a water-miscible solvent was employed, it is also possible to pour the mixture into water and extract the product.
3-Cyano-2,4-dihalogeno-5-fluoro-benzoic acid can be used, for example, for preparing the following compounds (VIII) known from U.S. Pat. No. 4,990,517:
7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,
methyl7-chloro-8-cyano-1-cyclopropyl-6-fluoro- 1 ,4-dihydro-4-oxo-3-quinolinecarboxylate,
8-cyano-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, ethyl 8-cyano-1 -cyclopropyl-6,7-difluoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylate.
To this end, for example, 3-cyano-2,4,5-trifluorobenzoic acid is reacted in the form of its acid chloride with the xcex2-dimethylamino-acrylic acid ester of the formula (V), and the resulting product of the formula (VI) is further reacted with cyclopropylamine to give a compound of the formula (VII), and the abovementioned compound (VII) is subsequently obtained: 
In the formula scheme above
X represents halogen, in particular fluorine or chlorine,
R6 represents C1-4-alkyl, in particular methyl or ethyl.
It is also possible to react a compound of the formula (IV) directly with xcex2-cyclopropylamino-acrylic acid ester: 
(In the formulae, X and R6 -are each as defined above.)
The acid chloride of 3-cyano-2,4,5-trifluorobenzoic acid can be prepared from the esters of the formula (IV) according to the following scheme: 
From the compounds of the formula (VIII), antibacterially active compounds can be prepared by reaction with suitable amines.
If, for example, 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 2,8-diazabicyclo[4.3.0]nonane are reacted, the course of the reaction can be represented by the formula scheme below: 
The preparation of these compounds is described in DE-A-196 33 805 of the applicant, which is not a prior art document.
The examples below illustrate the present invention without limiting its scope.